This application, entitled "Treatment of Bipolar Type II Major Depression," is a competing continuation grant that is predicated upon findings from our prior NIMH-funded study entitled "Relapse-Prevention of Bipolar Type II Disorder" (R01 MH060353). Bipolar type II (BP II) major depressive episode (MDE), the subject of this proposal, affects 2.5% of the US adult population and results in an estimated healthcare cost of $40 billion annually. BP II disorder is a distinct clinical entity that differs from BP I disorder, and is characterized by a preponderance of MDEs that result in particularly high morbidity and mortality rates. The treatment of BP II MDE remains a challenge for clinicians. Concerns over antidepressant drug (AD) induced manic switch episodes have led current practice guidelines to recommend treating BP II MDE with mood stabilizer (MS) monotherapy and to avoid AD monotherapy. To date, there are no controlled clinical trials to test the validity of these empirical guidelines. Results from our preliminary BP II MDE studies have shown that fluoxetine or venlafaxine monotherapy may be a safe and effective initial treatment of BP II MDE with a low manic switch rate. Based upon these observations, we now ask (Specific aim #1): "What is the relative safety and efficacy of initial AD monotherapy vs. MS monotherapy of BP II MDE?" and "What is the relative manic switch rate of initial AD vs. MS monotherapy ofBP II MDE?" To answer these questions, patients with BP II MDE will be treated in a 12-week, randomized, parallel group comparison of venlafaxine monotherapy vs. lithium monotherapy. We hypothesize that AD monotherapy will have superior efficacy vs. MS monotherapy, and that there will be a similar manic switch rate among both treatment conditions. We will also ask (Specific Aim #2): "What is the efficacy of continuation AD vs. MS monotherapy in BP II patients who have recovered from their MDE?" and "What is the manic switch rate during continuation AD vs. MS monotherapy for 6 months in recovered BP II MDE patients?" To answer this question, patients who have responded during initial therapy will receive 6-month continuation treatment of venlafaxine vs. lithium monotherapy. We hypothesize that AD monotherapy will have superior efficacy vs. MS monotherapy, and that there will be a similar manic switch rate among both treatment conditions. If our hypotheses are correct, we believe that these results may have an important public health impact on the current practice guidelines for treating BP II MDE.